Abstract Spine fusion surgery is associated with a significant failure rate (10-40%). A major potential cause is the presence of osteoporotic disease in the patient. The poor quality of osteoporotic bone can negatively impact upon healing after autografted spine fusion surgery. There are also multiple causes of osteoporosis;age and estrogen deficiency are leading candidates for the majority of patients, although gene haplotypes and other genetic variations may play roles. The following study is designed as a pilot investigation of the association of osteoporosis with poor outcome after spine fusion surgery. Two mouse lines which have highly characterized osteoporosis will be used together with a mouse spine fusion model developed by the PI, to determine causation of fusion failure with osteoporosis. One mouse line has greater numbers of osteoclasts due to a mutation in the SHIP gene, a modulator of osteoclast differentiation. The other mouse line has osteonectin deficiency, an extracellular matrix protein of bone that is necessary for normal bone integrity. Osteonectin-null mice have reduced numbers of both osteoblasts and osteoclasts, with a net reduction in bone density (i.e., osteoporosis). The study will test the hypothesis that osteoporosis is associated with a reduced response to spine fusion due to a defect in the bone graft or the vertebral bone or both. By using a cross-transplantation experimental design, effects of the bone graft can be separated from the recipient spine bone and circulating progenitor cells, thus permitting discrimination of osteoporotic influences on graft versus spine bone. Spine fusions will be evaluated at 1, 3, and 6 months to determine the time course for fusion under varying conditions of osteoporosis and the extent of remodeling of the fusion site. The results are expected to provide a better understanding of the influence of an osteoporotic state on response to spine fusion surgery. Future directions will include an in-depth investigation of the mechanistic aspects of fusion site bone remodeling under various conditions of osteoporosis, as well as investigations of therapeutic options for osteoporosis patients who require spine fusion surgery. Relevance Many patients with complications affecting the spine have osteoporosis as an additional component of their condition. The effect of underlying osteoporosis on the outcome of spine fusion surgery has been largely neglected in both experimental and clinical studies to date. Understanding how an osteoporotic predisposition influences spine fusion healing and remodeling is critical for developing better therapeutic options for these patients.